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Titolo:
Analysis of glucocorticoid and androgen receptor gene fusions delineates domains required for transcriptional specificity
Autore:
Whitacre, DC; Karnas, KJ; Miesfeld, RL;
Indirizzi:
Univ Arizona, Dept Biochem & Mol Biophys, Tucson, AZ 85721 USA Univ Arizona Tucson AZ USA 85721 chem & Mol Biophys, Tucson, AZ 85721 USA Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85721 USA Univ ArizonaTucson AZ USA 85721 ol & Cellular Biol, Tucson, AZ 85721 USA
Titolo Testata:
ENDOCRINE
fascicolo: 1, volume: 15, anno: 2001,
pagine: 111 - 118
SICI:
1355-008X(200106)15:1<111:AOGAAR>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
TUMOR VIRUS PROMOTER; STEROID-HORMONE RECEPTORS; AMINO-TERMINAL DOMAIN; LIGAND-BINDING DOMAIN; ONCOPROTEIN C-JUN; DNA-BINDING; TRANSACTIVATION DOMAIN; FUNCTIONAL ANTAGONISM; NUCLEAR RECEPTORS; RESPONSE ELEMENT;
Keywords:
glucocorticoid receptor; androgen receptor; steroid-regulated gene expression; transrepression; evolutionary divergence;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
63
Recensione:
Indirizzi per estratti:
Indirizzo: Miesfeld, RL Univ Arizona, Dept Biochem & Mol Biophys, Biol Sci W 518A, Tucson, AZ 85721 USA Univ Arizona Biol Sci W 518A Tucson AZ USA 85721 AZ 85721 USA
Citazione:
D.C. Whitacre et al., "Analysis of glucocorticoid and androgen receptor gene fusions delineates domains required for transcriptional specificity", ENDOCRINE, 15(1), 2001, pp. 111-118

Abstract

Androgen receptor (AR) and glucocorticoid receptor (GR) influence distinctphysiologic responses in steroid-responsive cells despite their shared ability to selectively bind in vitro to the same canonical DNA sequence (TGTTCT). While the DNA-binding domains (DBDs) of these receptors are highly conserved, the amino N-terminal domain (NTD) and hormone-binding domain (HBD) are evolutionarily divergent. To determine the relative contribution of these functional domains to steroid-specific effects in vivo, we constructed a panel of AR/GR gene fusions by interchanging the NTD, DBD, and HRD regions of each receptor and measured transcriptional regulatory activities in transfected kidney and prostate cell lines. We found that GR was approximately 10-fold more active than AR when tested with the mouse mammary tumor virus promoter, and that this difference in activity was primarily owing to sequence divergence in the NTDs. We also tested transcriptional activation of the androgen-dependent rat probasin promoter, and in this case, AR was at least twofold more active than GR. Analysis of the chimeric receptors revealedthat this difference mapped to the DBD region of the two receptors. Transcriptional repression functions of the wild-type and chimeric receptors weremeasured using an activator protein 1 (AP-1) transrepression assay and identified the GR HBD as a more potent transrepressor of AP-1 transcriptional activation than the AR HBD. Taken together, our analyses reveal that evolutionary sequence divergence between AR and GR functional domains results in unique promoter-specific activities within biologic systems in which both AR and GR are normally expressed.

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Documento generato il 18/02/20 alle ore 04:17:46